Human TRPA1 was first cloned from lung fibroblasts. TRPA1 was functionally characterized as a calcium permeable nonselective cation channel that is selectively localized to pain sensing peptidergic unmyelinated sensory neurons, which coexpress TRPV1, substance P and CGRP. TRPA1 exists in both peripheral and central terminals of sensory neurons Amino acid sequence comparison revealed that TRPA1 is a member of the transient receptor potential ion channel superfamily. A recent study finds a somewhat broader expression of TRPA1 even in myelinated fibers.
Studies in healthy animals suggest that TRPA1 is not activated under physiological conditions. Acute administration of TRPA1 agonists such as mustard oil and cinnamaldehyde to the skin causes acute pain and nocifensive behavior in healthy animals and man. Several pathophysiological conditions such as acute and chronic neuropathic pain, diabetes, cancer, inflammation, asthma, arthritis, migraine, osteoarthritis, sleep deprivation, and bladder dysfunction are known to have increased production of endogenous reactive compounds such as 4-hydroxynonenal, acetaldehyde, hydrogen peroxide, prostaglandin J2, prostaglandin A2, methylglyoxal, which are known to act as TRPA1 agonists. Interestingly, several TRPA1 agonists also can be produced through an oxidative stress-related non-enzymatic route.
TRPA1 is a nonselective catkin channel With substantial calcium permeability. TRPA1 is activated through an unusual mechanism in which reactive compounds bind covalently to cysteine and lysine amino acid residues in the N-terminus of the channel protein. Pathophysiological sustained TRPA1 activation by reactive agonists in sensory neurons may result in axoplasmic calcium dysregulation which causes peripheral axonopathy. Axonopathy is a common diagnostic finding in chronic pain patients and patients suffering from work-related exposure to neurotoxic compounds. Axonopathy of sensory neurons is often diagnosed in diabetic patients, who suffer from chronic pain, mechanical hypersensitivity, erectile dysfunction, impaired wound healing, numbness, and at later stage, from leg amputations.
Activation of presynaptic TRPA1 facilitates glutamate release from axon terminals of sensory neurons in the spinal cord. Enhanced glutamate release is shown to cause central pain and secondary mechanical hypersensitivity. Spontaneous pain, secondary mechanical hypersensitivity, and mechanical hyperalgesia are common symptoms of neuropathic pain patients. Recently, human TRPA1 gain-of-function mutation carriers were discovered and shown to have enhanced secondary hyperalgesia to peripheral TRPA1 stimulation, which confirms the role of spina TRPA1 in processing of secondary hyperalgesia. A recent study revealed that spinal TRPA1 plays a key role in neurogenic inflammation reflex, which is evoked by peripheral injury. Neurogenic inflammation is enhanced in several diseases such as fibromyalgia, migraine, complex regional pain syndromes, pain in and around the eye, and urticaria.
TRPA1 activation in the gastrointestinal tract has been shown to release serotonin from enterochromaffin cells. Increased serotonin release induces hypermotility of the gut. Treatment of cancer with reactive compounds increases plasma serotonin level, which is well known to induce nausea and vomiting. TRPA1 activation in airways has been shown to contribute to sensory neuronal hypersensitivity in several airway diseases such as chronic cough, asthma, and chronic obstructive pulmonary disease. TRPA1 activation has been shown to release noradrenaline from superior cervical ganglion sympathetic neurons. Several cardiovascular disorders such as cardiac dysrhythmias and high blood pressure, are well known to be caused by increased plasma noradrenaline level. TRPA1 has been shown to play a critical role in histamine-independent itch transduction. TRPA1 activation has been shown to result in cold hypersensitivity. Cold pain is a common symptom present in several disease conditions such as dental pain, fibromyalgia, complex regional pain, syndrome, cancer pain, and neuropathic pain. Selective TRPA1 modulators can be used for treatment of a large number of acute and chronic TRPA1 activation-dependent diseases and symptoms.
Various TRPA1 modulators have been described earlier, for example, in the international publications WO 2009/118596, WO 2009/144548, WO 2009/147079, WO 2010/004390, WO 2010/075353, WO 2010/109287, WO 2010/109329, WO 2010/109328, WO 2010/109334, WO 2010/125469, WO 2010/132838, WO 2010/138879, WO 2010/141805, WO 2011/043954, WO2011/132017, WO2011/114184 and WO2012/085662. WO2004/060286 discloses certain benzamide derivatives for the treatment of pain and traumatic injury.